2-cyclohexylalkanoyl-1-(tertiary-amino)-cycloalkenes

ABSTRACT

2-Cyclohexylacetyl-1-BN-cyclohexene, 2-cyclohexylacetyl-1-BNcyclopentene and 2-(3-cyclohexylpropanoyl)-1-BN-cyclopentene are prepared respectively by reacting cyclohexylacetyl halide with 1BN-cyclohexene or 1-BN-cyclopentene or reacting 3cyclohexylpropanoyl halide with 1-BN-cyclopentene, where BN is morpholino, piperidino, pyrrolidino or di-(lower-alkyl)amino. These compounds are intermediates for the preparation of 2hydroxy-3-(8-cyclohexyloctyl)-1,4-naphthoquinone and 2-hydroxy-3(7-cyclohexylheptyl)-1,4-naphthoquinone, which are potent antimalarial agents.

United States Patent New York, N.Y.

Continuation-impart of application Ser. No. 589,201, Oct. 25, 1966, now Patent No. 3,523,959.

[5 4] Z-CYCLOHEXYLALKANOYL-l -(TERTIARY- AMlN0)-CYCLOALKENES 2 Claims, No Drawings [52] US. Cl ..260/247.7K, 260/294.7 J, 260/326.5 J, 260/413, 260/563 R, 260/999 [51] Int. Cl C07d 87/34 [50] Field of Search 2150/3265 J, 247.7 K, 294.7 J, 563 R Primary Examiner-Alex Mazel Assistant Examiner-Jose Tovar Attorneys-Elmer J. Lawson, B. Woodrow Wyatt, Thomas L. Johnson, Robert K. Bair, William G. Webb and Roger T. Wolfe ABSTRACT: 2-Cyclohexylacetyl-l-BN-cyclohexene, 2- cyclohexylacetyl-l-BN-cyclopentene and 2-(3-cyclohexylpropanoyl)-l-BN-cyclopentene are prepared respectively by reacting cyclohexylacctyl halide with l-BN-cyclohexenc or 1- BN-cyclopentene or reacting 3-cyclohexylpropanoyl halide with l-BN-cyclopentene, where BN is morpholino, piperidino, pyrrolidino or di-(lower-alkyl)amino. These compounds are intermediates for the preparation of 2-hydroxy-3-( 8-cyclohexyl0ctyl)-l,4-naphthoquinone and 2-hydr0xy-3-(7-cyclohexylheptyl)-l,4-naphthoquinonc, which are potent antimalarial agents.

Z-CYCLOHEXYLALKANOYL-l-(TERTlARY-AMINO)- CYCLOALKENES This application is a continuation-in-part of our copending application Ser. No. 589,201 filed Oct. 25, 1966 now Pat. No. 3,523,959, issued Aug. 11,1970.

This invention relates to intermediates for preparing 2- hydroxy3-(8-cyclohexyloctyl)-l,4-naphthoquinone and 2- hydroxy-3-7-cyclohexylheptyl)-l, 4-naphthoquinone, which are potent antimalarial agents.

The invention sought to be patented resides in the following compounds: 2-cyclohexylacetyl-l-BN-cylcohexene, 2- eyclohexylacetyl-l-BN-cyclopentene and 2-(3-cyclohcxylpropanoyl -l-BN-cyclopentene where BN is morpholino, piperidino, pyrrolidino or di-(lower-alkyl)amino.

The preparation of the above compounds and their use in the preparation of said antimalarial agents are given in the process which comprises the steps of: reacting cyclohexylacetyl halide with l-BN-cyclohexene or l-BN-cyclopentene or reacting 3 -cyclohexylpropanoyl halide with l-BN- cyclopentene to form 2-cyclohexylacetyl-l-BN-cyclohexene, 2-cyclohexylacetyl-l-BN-cyclopentene and 2-(3-cyclohexylpropanoyl-l-BN-cyclopentene respectively where BN is morpholino, piperidino, pyrrolidino or di-(lower-alkyl)- amino; heating the 2-acyl-l-BN-cycloalkene in an acidic aqueous medium to form 2-cyclohexylacetylcyclohexanone, 2- cyclohexylacetylcyclopentanone and 2-(3-cyclohexylpropanoyl)-cyclopentanone respectively; heating the 2-acylcycloalkanone in an aqueous alkaline medium to form 8- cyclohexyl-7-keto-octanoic acid, 7-cyclohexyl-6-ketoheptanoic acid and 8-cyclohexyl-6-ketooctanoic acid respectively; and, reducing the cyclohexyl-keto-alkanoic acid to yield 8- cyclohexyloctanoic acid, 7-cyclohexylheptanoic acid and 8- cyclohexyloctanoic acid respectively. The above process is disclosed and claimed in said copending application Ser, No. 589,201.

The term lower-alkyl, as used throughout this specification, means an alkyl radical having from one to six carbon atoms inclusive, illustrated by methyl, ethyl, isopropyl, npropyl, n-butyl, sec-butyl, isobutyl, n-amyl, n-hexyl, and the like.

The cyclohexyalkanoic acids produced by the above process are useful in the preparation of 2-hydroxy-3-(8- cyclohexyloctyl-1,4-naphthoquinone or 2-hydroxy-3- (7- cyclohexylheptyl)-l,4-naphthoquinone by: reacting 8- cyclohexyloctanoic acid or 7-cyclohexylheptanoic acid with l'naphthol to form 2-(8-cyclohexyloctanoyl)-l-naphthol or 2- (7-cyclohexylheptanoyl)-l-naphthol respectively; reducing the 2-acyll naphthol to form 2-(8-cyclohexyloctyl)-lnaphthol or 2-(7-chclohexylphetyl)-l-naphthol respectively; oxidizing 2-(8-cyclohexyloctyl)- l-naphthol or 2-(7-cyclohexylheptyl)-l-naphthol to form 2-(8-cyclohexyloctyl)1,4- naphthoquinone or 2(7-cyclohexylheptyl)-l,4-napthoquinone respectively; reacting the 2-(cycloalkylalkyl)-l,4- naphthoquinone with a peroxide under alkaline conditions to form 2-(8-cyclohexyloctyl)-l,4-naphthoquinone2,3-oxide or 2-(7-cyclohexylheptyl)-l ,4-naphthoquinone -2,3-oxide respectively; and, hydrolyzing the 2,3-oxide under acidic conditions to yield 2-hydroxy-3-(8-cyclohexyloctyl)-l,4- naphthoquinone or 2-hydroxy-3-(7-cyclohexylheptyl)-1,4- naphthoquinone respectively.

The manner and process of making and using the instant invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:

PROCESS OF lNVENTION The reaction of cyclohexylacetyl halide with l-BN- cyclohexene or l-BN-cyclopentene or the reaction of 2 cyclohexylpropanoyl halide with l-BN-cyclopentene to form 2-cyclohexylacetyl-l-BN-cyclohexene, 2-cyclohexylacetyl-l- BN-cyclopentene or 2-(3-cyclonexylpropanoyl)-lBN- cyclopentene respectively is carried out by mixing said reactants, using the acyl chlorides preferably, in a suitable inert solvent, e.g., chloroform, dioxane, benzene, etc. and in the presence of an acid-acceptor, e.g., triethylamine, pyridine, dimethylaniline, potassium carbonate, sodium carbonate, etc., while maintaining the temperature of the reaction mixture between about 0to 50 C., preferably between about 25to 40 C. The reaction mixture containing 2-cyclohexylacetyl-l- BN-cyclohexene, 2-eyclohexylaeetyl-l-BN-cyclopentene or 2- (3-cyclohexylpropanoyl)l-BN-cyclopentenc is then heated, preferably refluxing while stirring, with an aqueous solution containing a mineral acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc. to convert the 2- cyclohcxyl-acyl-l-BN-cycloalkene to 2-cyclohexylacetyl cyclohexanone, 2-cyclohexylacetylcyclopentanone or 2-(3- cyclohexylpropanoyl)- cyclopentanone respectively. Preferred embodiments in the above steps are those where BN is morpholino. The conversion of the 2-acylcycloalkanone to the corresponding cyclohexylketoalkanoic acid is effected by heating the 2-cyclohexyl-acyl-cycloalkanone in an aqueous alkaline medium, e.g., aqueous potassium or sodium hydroxide solution. The resulting cyclohexyl-ketoalkanoic acid is readily reduced by heating it in a suitable solvent, e.g., a water-soluble solvent boiling between about l-250 C., preferably between about l80220 C., e.g diethylene glycol, with hydrazine hydrate and subsequent hydrolysis of the resulting hydrazone by heating in the same solvent to form 8cyclohexyloctanoie acid or 7cyclohexylheptanoic acid as indicated above; the formation of the hydrazone was carried out by heating the reactants at about l0O-l40 C., preferably about 1 lS-l 25 C., and the hydrolysis of the hydrazone was accomplished by heating it at about l60-250 C., preferably about l80-225 C. Alternatively, but less preferred, the reduction can be run using zinc amalgam and concentrated hydrochloric acid.

USE OF PRODUCTS OF ABOVE PROCESS The reaction of 8-cyclohexyloctanoic acid of 7-cyclohexylheptanoic acid with l-naphthol to form 2(8-cyclohexyloc tanoyl or 7-cyclohexylheptanoyl)-l-naphthol is run by heating the reactants in the presence of a condensing agent, e.g., BF or ZnCl preferably in boron trifluoride etherate at about 95 C. Heating temperatures in the range of about 80to l20C. can be used. The reduction of 2-(8-cyclohexyloctanoyl or 7- cyclohcxylheptanoyl)-l-naphthol is carried out by heating it with amalgamated zinc and concentrated hydrochloric acid, preferably refluxing in a suitable solvent, e.g., methanol, ethanol, acetic acid, etc., to yield 2-(8-cyclohexyloctyl-lnaphthol or 2-(7-cyclohexylheptyl)- l -naphthol.

2-(8-Cyclohexyloctyl or 7-cyclohexylheptyl)-l-naphthol is converted to 2-(8-cyclohexyloctyl or 7-eyclohexylhcptyl)- l ,4- naphthoquinone either in one step by direct oxidation or in four steps via its 4-amino derivative. The direct oxidation is carried out by heating at about 50to 80C., preferably about 60to 70 C., 2(8-cyclohexyloctyl or 7-cyclohexylheptyl)-lnaphthol with chromium trioxide, i.e., CrO in a suitable solvent, e.g., acetic acid containing about 5 to 50 percent water.

Said four-step conversion is carried out by first reacting 2 (8-cyclohexyloctyl or 7-cyclohexylheptyl)-l-naphthol with a diazotized salt of sulfanilic acid to form 2-(8-cyclohexyloctyl or 7-cyclohexylheptyl)4-(4-sulfophenylazo)-l-naphthol. The azo compound is reduced to the corresponding 4-amino compound, preferably using sodium hydrosulfite (Na S O,) in aqueous methanol solution; the reduction also can be run using zinc and hydrochloric acid. The 4-amino compound, in a suitable solvent, e.g., acetic acid, is oxidized to 2-(8-cyclohexyloctyl or 7-cyclohexylheptyl)-1,4-dihydro-4-imino-l-oxonaphthalene using chromium trioxide in aqueous acetic acid, preferably in the presence of sulfuric acid and then hydrolyzing the 4-imino sulfate salt in situ by heating the acidic reaction mixture at about 60 to C. to yield 2-(8-cyclohexyloctyl or 7-cyclohexylheptyl)-l ,4-naphthoquinone. Alternatively, by using no sulfuric acid during the oxidation, the 4-imino compound can be isolated as its'chromate salt which is then hydrolyzed under acidic conditions, preferably by treating a hot aqueous acetic acid solution of the imino salt with a mineral acid, e.g., hydrochloric acid or sulfuric acid.

The reaction of 2-(8-cyclohexyloctyl or 7-cyclohexylheptyl )l ,4-naphthoquinone to form its 2,3-oxide is carried out by reacting the former compound with a peroxide, e.g., hydrogen peroxide, under alkaline conditions, e.g., aqueous potassium or sodium hydroxide, preferably using a suitable organic solvent, e.g., tertiary-butanol, dioxane. The slightly exothermic reaction is run without any external heating. The 2,3-oxide is hydrolyzed under acidic conditions to produce 3-(8-cyclohexyloctyl or 7-cyclohexylheptyl)-2-hydroxy-l,4-naphthoquinone, the hydrolysis preferably being carried out by dissolving the oxide in concentrated sulfuric acid, adding this solution to a mixture of water (or ice) and acetic acid, and then heating the reaction mixture on a steam bath.

The direct oxidation of 2-(8-cyclohexyloctyl or 7-cyclohexylheptyl)-l -naphthol as its alkali metal salt to form Z-hydroxy- 3-( 8-cyclohexyloctyl or 7-cyclohexylhcptyl l ,4- naphthoquinone is carried out preferably by passing oxygen into a stirred mixture containing said 2-(cyclohexylalkyl)-lnaphthol and an excess (more than 1 and preferably from 2 to 3 moles per mole of said l-naphthol of an alkali metal (e.g., potassium or sodium) t-butoxide in t-butanol, the mixture being kept between about l5to 40 C., preferably about 20to 30C.

The best mode contemplated for carrying out the invention will now be set forth, as follows:

Cyclohexaneacetyl chloride A solution of 430 g. cyclohexaneacetic acid in 1,000 ml. of chloroform was added to 430 g. (3.6 moles) of thionyl chloride at such a rate as to maintain gentle reflux. After the addition was completed the reaction was refluxed for 2 hours. The chloroform was removed in vacuo and the residue was distilled. A total of 432 g. (90 percent) of colorless oil, b.p. 88-92 CH 8 mm., was collected.

l-Morpholinocyclohexene A solution of 180 g. (2.04 moles) of morpholine, 196 g. (2.00 moles) of cyclohexanonc, 400 ml. of benzene and 1.0 g. of p-toluenesulfonic acid was refluxed for twenty hours, during which time a total of 39 ml. of water was collected. The benzene was removed under vacuum and the residue was distilled. A total of 265 g. (79 percent) of product, hp. 1 l4-l 16 C./] 2 mm., was collected.

Following the above-described procedure for the preparation of l-rnorpholinocyclohexene but using piperidine, pyrrolidine, dimethylamine, diethylamine, di-n-propylamine or di-n-hexylamine in place of morpholine, there is obtained, respectively, l-piperidinocyclohexene, l-pyrrolidinocyclohexene, ldimethylaminocyclohexene, l-diethylaminocyclohexene, l-di-n-propylaminocyelohexene or l-di-n-hexylaminocyclohexene. Following the above procedure for the preparation of l-morpholinocyclohexene and using cyclopentanone in place of cyclohexanone and using morpholine, piperidine or diethylamine, there is obtained, respectively, 1- morpholinocyclopentene, l-piperidinocyclopentene or 1- diethylaminocyclopentene.

2-Cyelohexylacetylcyclohexanone A solution of 288 g. (1.72 moles) of freshly prepared 1- morpholinocyclohcxene, and 188 g. (1.87 moles) of triethylamine (dried over KOH) in 1,000 ml. of chloroform was treated over a period of l30 minutes with a solution of 273 g. (l.70 moles) of cyclohexaneacetyl chloride in 500 ml. of chloroform while maintaining the temperature at 2835 C. by means of a water bath. During the addition, the system was protected with a calcium chloride drying tube. immediately following the addition, the reaction mixture was stored at 4 C. for 16 hours. The light yellow solution containing 2-cyclohexylacetyl-l-morpholinocyclohexene was treated with a solution of 225 ml. (2.7 moles) of concentrated hydrochloric acid in 550 ml. of water and the two-phase system was refluxed for 2 hours while stirring rapidly. The mixture was cooled and separated. The chloroform solution was washed with water, 5 percent sodium bicarbonate solution and twice more with water (to obtain a pH of 7.0). The chloroform was removed under vacuum. The fraction boiling at l28l3l C./0.05 mm. was collected to yield 275 g. (72 percent) of 2-cyclohexylacetylcyclohexanone as a light yellow oil.

Following the above procedure for the preparation of 2- cyclohexylacetylcyclohexanone but using l-piperidinocyclohexene, l-pyrrolidinocyelohexene, l-dimethylaminocyclohexene, l-diethylaminocyclohexenc, l-di-npropylaminocyclohexcne, 1'di-n-hexylaminocyclohexene, lmorpholinocyclopentene, l-piperidinocyclopentene or I- diethylaminocyclopentene, in place of l-morpholinocyclohexene, there is first obtained, respectively, 2-cyclohexylacctyll 4 piperidinocyclohexene, 2-cyclohexylacetyl-lpyrrolidinocyclohexene,2-cyclohexylacetyll -dimcthylaminocyclohcxcne, 2-cyclohexylacetyl-l-diethylaminocyclohcxcne, 2- cyclohexylacetyll -di-n-propylaminocyclohcxene, 2- cyclohexylacetyl-ldi-n-hexylaminocyclohexene, 2-cyclohexylacetyll -morpholinocyclopentene, Z-cyclohexylacetyll piperidinocyclopentene or Z-cyclohexylacetyll diethylaminocyclopentene, each of which is then converted on acid hydrolysis, as above, to yield 2-cycl0hexylacctylcyclohexanone from said cyclohexene derivatives and 2- cyclohexylacetylcyclopentanone from said cyclopentene derivatives. Following the above procedure for the preparation of 2-cyclohexylacetylcyclohexanone but using 1- morpholinocyclopentene, l-piperidinocylopentene or 1- diethylaminocyclopentene in place of l-morpholinocyclohexene and 3-cyclohexylpropanoyl chloride in place of cyclohexylacetyl chloride, there is first obtained, respectively 2-( 3- cyclohexylpropanoyl l -morpholinocyclopentcne, 2-( 3- cyclohexylpropanoyl)-l-piperidinocyclopentene or 2-(3- cyclohexylpropanoyl)-l-diethylaminocyclopentene, each of which on acidic hydrolysis as above yields 2-(3-cyclohexylpropanoyl) cyclopentanone.

8-Cyclohexyl-7-ketooctanoic Acid A solution of 190 g. (3.4 moles) of potassium hydroxide in 1,000 ml. of water was heated to reflux in a 3-liter three-neck flask. With vigorous stirring 275 g. (1.23 moles) of 2- cyclohexyiacetylcyclohexanonc was added over a period of several minutes while maintaining reflux temperature. The light yellow reaction mixture immediately became homogenous and it was quickly cooled in ice. While cooling and stirring, the reaction mixture was acidified slowly whereby the product precipitated. After cooling to l0 C the product was filtered and dried at 35 C. in vacuum for 20 hours. A total of 298 g. percent) of the white crystalline 8-cyclohexyl- 7-ketooctanoic acid, m.p. 6 l 63 C., was obtained.

Following the above-described procedure for the preparation of S-cyclohexyl-7-ketooctanoic acid by using 2-(3- cyclohexylpropanoyl) cyclopentanone or 2-cyclohexylacetylcyclopentanone in place of 2-cyclohexylacetylcyclohexanone, there is obtained 8-cyclohexyl-6acid or 7-cyclohexyl-6- ketoheptanoic acid respectively.

8-Cyclohexyloctanoic Acid A solution of 23.7 g. (0.089 mole) of 8'cycl0hexyl-7- ketooetanoic acid, 16 ml. of 85 percent hydrazine hydrate and 150 ml. of diethylene glycol was heated at [20 C. for 4 hours. The solution was cooled to about 60 C., excess water and hydrazine hydrate was removed under vacuum while raising the temperature back to C. The cloudy, buff colored solution was again cooled to about 60 C. and 25 g. of potassium hydroxide was added. Under a nitrogen atmosphere, the temperature of the mixture was raised to 220 C. over a period of 1% hours. The temperature was maintained at 220 C. until the solution just started to darken (approximately 30 minutes); the solution was then carefully poured into about three volumes of ice and water. After the mixture was acidified with concentrated hydrochloric acid, it was extracted three times with ether. The combined ether extracts were dried over CaCl charcoaled and concentrated in vacuum. The light brown residue, which readily crystallized,

weighted 17.2 g. (87 percent). The crude product was recrystallized from methanol, using a dry iceacetonc bath. The filtration was carried out in the refrigerator since the product readily redissolved at room temperature. The yield was 15.0 g. (75 percent) of 8cyclohexyloctanoic acid, m.p. 4l42C.

8Cyclohexyloctanoic acid is also obtained following the abovedescribed procedure but using 8-cyclohexyl-6-ketooctanoic acid in place of 8-cyclohexyl 7-ketooctanoie acid; 7- cyclohexylheptanoic acid is obtained using 7-cyclohexyl-6- ketoheptanoic acid in place of 8-cyclohexyl-7-ketooctanoic acid.

2-(8-Cyclohexyloctanoyl)-l-naphthol A solution of 43.9 g. (0.193 mole) of 8-cyclohexyloctanoic acid and 29.3 g. (0.203 mole) of a-naphthol in 125 ml. of boron trifluoride etherate (47 percent) was stirred and heated on a steam bath for 1 hour. A total of 200 ml. of water was added carefully but fairly rapidly while a vigorous evolution of ether ensued. The mixture was cooled and an additional 250 ml. of water was added. The product was extracted with chloroform. The extracts were washed twice with water, dried over CaCl and charcoaled, and finally concentrated in vacuum. The brown residue, which weighed 82.0 g., crystallized on cooling. The crude product was slurried in 300 ml. of cold methanol and collected; the bright yellow precipitate was washed with about 50 ml. of cold methanol. After drying 16' hours at 30 C. in vacuum, the product, 2-(8cyclohexyloctanoyl)-1-napthol, weighed 51.2 g. (75 percent) and melted at 8687 C. 2-(8-cyclohexyloctanoyl)-l-naphthol when tested by standard in vitro antibacterial procedures was found to have antibacterial activity, thereby indicating its further use as an antibacterial agent.

Following the above-described procedure but using 7- cyclohexylheptanoic acid in place of 8-eyclohexyloctanoic acid, there is obtained 2-(7-cyclohexylheptanoyl)-1-naphthol.

2-(8-Cyclohexyloctyl)-1-naphthol A mixture of 24.3 g. (0.069 mole) of 2-(8-cyclohexyloctanoyl)-1-naphthol, 100 g. of amalgamated zinc, 500 ml. of methanol and 100 ml. of concentrated hydrochloric acid was refluxed while stirring vigorously for 1 hour. An additional 100 ml. of concentrated hydrochloric acid was added and refluxing was continued for 2 hours. The volume was reduced to about 250 ml. in vacuo and then diluted with 200 ml. of water. The product was extracted with ether; the extracts were combined, dried over CaCl and concentrated. The residue was crystallized from n-pentane by cooling in a dry iceacetone bath. The product was dried at room temperature under vacuum to yield 19.5 g. (84 percent) of 2-(8-cyclohexyloctyl)-1-naphthol, m.p. 38-39 C.

Following the above-described procedure for the preparation of 2-(8-cyclohexylocytyl)-l-naphthol but using 2-(7- cyclohcxylheptanoyl)-l-naphthol in place of 2-(8-cyclohexylocatnoyl)-l-naphthol, 2-(7-cyclohexylhepty1)-l-naphthol is obtained.

2-(8-Cyclohexyloctyl)4naphthoquinone (via 4amino-lnapthol) A mixture of 23.4 g. (0.135 mole) of sulfanilic acid and 7.2 g. (0.0675 mole) of sodium carbonate in 135 ml. of water was heated until the materials were in solution. The solution was cooled to about C. and a cold solution of 10.2 g. (0.147 mole) of sodium nitrite in 27 ml. of water was added. The resulting solution was poured at once into a mixture of 30 ml. of concentrated hydrochloric acid and 160 g. ofice. The reaction was allowed to stand in an ice bath for minutes. In a 2- liter, three-neck flask 45.9 g. (0.135 mole) of 2-(8-cyclohexyloctyl)-l-naphthol in 270 ml. methanol was treated with a solution of 30 g. of sodium hydroxide in 120 ml. of water and the slurry was cooled to C. The suspension of the diazonium salt was then added, using 45 ml. of methanol to wash it in. The resulting purple solution containing 2-(8-cyclohexyloctyl)-4-(4-sulfophenylazo)-1-naphthol was stirred for 20 minutes. After heating the solution to 40 C. on a steam bath, a slurry of 67.2 g. of sodium hydrosulfite (Na S O in 200 ml.

of water was added cautiously and the temperature of the mixture was raised to C. The reaction mixture turned bright yellow within minutes and it was stirred for fifteen minutes without additional heating. The 4-amino-2-(8-cyclohexyloctyl)-l-naphthol was collected and washed with water. To oxidize said 4aminonaphthol, the moist precipitate was suspended in 350 ml. of acetic acid and the suspension was added fairly rapidly to stirred solution of 30 g. of chromium trioxide (CrO in 300 ml. of acetic acid and 60 ml. of water while maintaining the temperature of 60 C. After 5 minutes the mixture was cooled and the precipitate collected. The brown crystalline 2-(8-cyclohexyloctyl)-1,4dihydro-4-iminol-oxonaphtalene chromate salt was placed in a desiccator overnight. The imine salt was hydrolyzed by dissolving it in 250 ml. hot acetic acid and adding 250 ml. concentrated hydrochloric acid to the solution. After cooling, the reaction mixture was poured into 500 ml. of water. The crystalline product that separated was collected and recrystallized from absolute ethanol to yield 32.0 g. (67 percent) of light brown crystalline 2-(8-cyclohexyloctyl)-1,4-naphthoquinone, m.p. 82-83 C.

In another run of the above-described procedure, a preferred modification was the oxidation of the 4- aminonapthol as its sulfate salt, said modification being illustratcd as follows: To a solution (cooled to 20 C.) containing 1.4 liters of water, 700 ml. of concentrated sulfuric acid, 4.1 liters of acetic acid and 415 g. of chromium trioxide was added, with external cooling, a slurry of 4-amino-2-(8- cyclohexyloctyl)-lnaphthol [obtaine as above through the azo compound from 637 g. of 2-(8-cyclohexyloctyl)-l-naphthol] in four liters of acetic acid whereupon the temperature of the reaction mixture rose to 45 C. The reaction mixture was then heated on a steam bath; after the temperature had reached 87 C., 6 liters of water were added to the reaction mixture which was cooled to 8 C. The resulting crystalline precipitate was collected, washed with a total of 6 liters of water, and dried at room temperature in vacuo over the weekend (68 hours) to 600 g. (91 percent) of 2-(8-cyclohexyloctyl)-1,4- naphthoquinone, m.p. 79 81C.

Following theabove-described procedure but starting with 2-(7-cyclohexylheptyl)-l-naphthol instead of 2-(8-cyclohexyloctyl)-1-naphthol, there are obtained respectively 2(7- cyclohexylheptyl)-4(4-sulfophenylazo)-l-naphthol, 4-amino- 2-(7-cyclohexylheptyl)-l-naphthol, 2-(7-cyclohexylheptyl)- l,4-dihydro-4-imino-l-oxonaphthalene (as chromate or sulfate salt), and 2-(7-cyclohexylheptyl)- 1,4-napthoquinone.

2-( 8-Cyclohexyloctyl)-l ,4-napthoquinone-2,3-oxide To a suspension of 7.7 g. (0.0228 mole) of 2(8-cyclohex yloctyl)-l,4-naphthoquinone, 1.3 g. (0.0232 mole) of potassium hydroxide in 20 ml. of water, and ml. of tertiary-butanol was added 7.7 ml. of 30 percent hydrogen peroxide and the mixture was stirred at room temperature for one hour (the reaction was slightly exothermic). The mixture was poured into tow volumes of water, cooled and filtered. The product was washed well with water and then dried at 30 C. in vacuo. The slightly pink crystalline 2-(8-cyclohexyloctyl)-l,4- napthoquinone-2,3-oxide weighed 6.9 g. (82 percent) and melted at 5153 C. 2-(8-cyclohexyloctyl)-l,4-napthoquinone-2,3-oxide when tested by standard antimalarial testing procedures in mice infected with Plasmodium berghei was found to have antimalarial activity, thereby indicating its further use as an antimalarial agent.

Following the above-described procedure but using 2-(7- cyclohexylheptyl)-1,4-naphthoquinone, there is obtained 2- (7-cyclohexylheptyl)-l ,4-naphthoquinone-2,3-oxide.

2-Hydroxy-3-(8-cyclohexyloctyl)-1,4-naphthoquinone A total of 30 g. (0.0814 mole) of 2-(8-cyclohexyloctyl)-1,4- naphthoquinone-2,3-oxide was added slowly to ml. of concentrated sulfuric acid while maintaining the temperature at about 5 C. The mixture was allowed to warm to room tem perature. After the solution became homogeneous it was poured into a solution of 200 g. of ice in 600 ml. of glacial acetic acid. The mixture was heated on a steam bath for 1 hour, then cooled and filtered. The crystalline product was charcoaled and recrystallized twice from methanol to yield 24.0 g. (80 percent) of 2-hydroxy-3-(B-cyclohexylocty])-l,4- naphthoquinone, m.p. 77-79C.

Following the above procedure but using 2-(7-cyclohexylheptyl)-l,4-naphthoquinone-2,3-oxide, there is obtained 2- hydroxy-3-(7-cyclohexylheptyl)-1,4-naphthoquinone.

2-( 8-Cyclohexyloctyl)-l,4-naphthoquinone (by direct oxidation of 2-(8-cyclohexyloctyl)-l-napthol) To a solution of 3.42 g. of 2-(8-cyclohexyloctyl)-l -naphthol in 25 ml. of acetic acid was added dropwise with stirring over a period of ten minutes a solution of 4 g. of chromium trioxide in a mixture of 4 ml. of acetic acid and 4 ml. of water. The reaction mixture was heated in a water bath at about 63to 71 C. for five hours and then poured into 2% volumes of water. The aqueous mixture was extracted with ether. The ether extract was dried over anhydrous sodium sulfate and heated in vacuo to remove the ether. The residue was dissolved in 30 ml. of ethanol and the ethanolic solution cooled. The resulting precipitate was collected to yield 1.3 g. of 2-(8-cyclohexyloctyl)-l,4-naphthoquinone, m.p. 798l C. The filtrate was concentrated to a volume of about ml. and cooled to yield another 0.3 g. of said product.

In another run, a solution of8.0 g. of chromium trioxide in 8 ml. of acetic acid and 10 ml. of water was added dropwise with stirring over a period of minutes to a solution of 6.8 g. of 2- (8cyclohexyloctyl)-l-naphthol in 50 m]. of acetic acid, with the temperature of the reaction mixture rising to 55 C. during the addition. The reaction mixture was then allowed to cool to room temperature (35 C.), stirred for 17 hours, and poured into 300 ml. of water, whereupon some crystalline product separated immediately. The mixture was cooled to l5 C., and the product collected and recrystallized from methanol to yield 3.0 g. of 2-( 8-cyclohexyloctyl)-l ,4-naphthoquinone, m.p. 82-83 C. A second crop of product, m.p. 7880 C., was obtained from the filtrate.

Following the above procedure but using 2-(7-cyclohexylheptyl)-l-naphthol in place of 2-( 8-cyclohexyloctyl)'lnaphthol, there is obtained 2-(7-eyclohexylheptyl)-[,4- naphthoquinone.

2-Hydroxy-3-(8-eyclohexyloctyl)-l,4-naphthoquinone (by direct oxidation 2-(8-cyclohexyloctyl)-l -napthol) A solution of 0.83 g. (7.5 moles) of potassium tertiary-butoxidc in 25 ml. of tertiary-butanol was added to a solution of L0 g. (3 moles) of 2-(8-cyclohcxyloctyl)-l-naphthol in 20 ml. of tcrtiary-butanol. While stirring rapidly, oxygen was passed into the mixture for 3 hours. The dark red solution was poured into water, acidified with concentrated hydrochloric acid and extracted three times with n-pentane. The combined pentane extracts were then extracted with dilute aqueous sodium hydroxide solution containing 20 percent methanol. The basic extracts were washed twice with n-pentane. The aqueous layer was acidified and again extracted with n-pentane. The pentane extracts were charcoaled, dried over anhydrous magnesium sulfate and concentrated. The residue, 0.38 g., was dissolved in 5 ml. of methanol and after cooling to 40 C., the gummy precipitate was filtered. After one recrystallization from methanol, there was obtained 0.l9 g. (18 percent) of 2- hydroxy-3-(8-cyclohexyloctyl)-1,4-naphthoquinone, m .p. 77-79 C. This compound was found to be identical with the 2-hydroxy-3-( 8-cyclohexyloctyl)-l ,4-naphthoquinone obtained by the above-described hydrolysis of 2-(8-cyclohexyloctyl)-l,4-naphthoquinone-2,3-oxide, e.g., a mixed melting of the two samples showed no depression.

Following the above procedure for the direct oxidation of 2- (8-cyclohcxyloctyl)-l-naphthol to 2-hydroxy3(8-cyclohexyloctyl)-l,4-naphthoquinone but using 2(7cyclohexylhep tyl)-l-naphthol, there is obtained 2-hydroxy-3-( 7-cyclohexylheptyl )-l ,4-naphthoquinone.

2-Hydroxy-3-(8-cyclohexyloctyl)- l ,4-naphthoquinone and 2-hydroxy-3-(7-cyclohexylheptyl)-l,4-naphthoquinone were found to have useful antimalarial activity when tested by standard chemotherapeutic procedures against plasrnodialinfectrons in animals, e.g., against Plasmodzum berghez infections in mice; their activity was significantly greater than the antimalarial activity for previously known and tested 2-hydroxy- 3-cyclohexylalkyl-l,4-naphthoquinones which had been prepared by different procedures than disclosed herein.

The subject matter which the applicants regard as their invention is particularly pointed out and distinctly claimed as follows:

1. A compound selected from Z-cyclohexylacetyl-l-BN- eyclohexene, 2-cyclohexylacetyl-l-BN-cyclopentene and 2piperidino, 3-cyclohexylpropanoyl)-l BN-cyelopentcne where BN is morpholino, piperdino, pyrrolidino or di(loweralkyl) amino.

2. 2-Cyclohexylacetyl-l-morpholinocyclohexenc according to claim 1 where BN is morpholino.

(5/69? a a Y s CEH'EiFMIATLL OF (AN? LHnC .Ev UR Patent No. 5. 607 871 Q Dated September 2] 1971 Inventorfs) Sydney Archer 80 Roman R. Lorenz It is certified that error appears in the above-id dtified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 8, "5-?" should read 3- (7 line 11, "cylcohexene" should read cyclohexene line 13, propanoyl-d" should read propanoyl -l line 22, "propanoyl-l" should read propanoyl -l line 42, "cyclohexyalkanoic" should read cycloheaqrlalkanoic line 4 4, "cyclohexyloctyl-l, should read ClfClOhGXYlOCtYlj-l,

line 50, "'f-chclohexylphetyl" should read 'i-cyclohexylheptyl line 52, ")1, should read l, n line 73, "cyclonexylpropanoyl" should read cyclohexylpropanoyl Column 2, line 38, "of" (second occurrence) should read or line 48, "cyclohexyloctyl-l" should read cyclohexyloctyl)-l Column 3, line 37, "92 C. should read 92C. Column line 29, "piperidinocylooentene should read piperidinocyclo; pentene line 53, by should read but line 56, "acid" should read ketooctanoic acid Column 5, line 1,

"17a" should read 17.5 line 50, "87 c. should read 87C. line 55, "ylocatnoyl) should read yloctanoyl) line 57, lnaphthoquinone should read -1, l-naphthoquinone Column 6, line 8, "to stirred" should read to a stirred line 10, of" should read at line 15, "oxonaohtalene" should read oxonaphthalene line 30, "obtaineshould read obtained line 56, "tow" should read two Column 8, line 22, 5(8" should read -3-(8 line no, "Qpiperidino,

B-cyclohexylprozanoyl)-lBN-" should read 2- (3-cyclohexylpropanoyi l-BN- line 'piperdino" should read piperidino Signed and sealed this llth'day of April 1972.

(SEAL) Attest:

-EDWARD MELETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

2. 2-Cyclohexylacetyl-1-morpholinocyclohexene according to claim 1 where BN is morpholino. 